Malignant cells are continuously exposed to extrinsic (hypoxia, limited access to nutrients, immune surveillance) and intrinsic (oncogenic insults) stresses that culminate in activation of the hypoxia and endoplasmic reticulum stress (ERS) response programs. Tumor cell adaptation to these challenges depends on both genetic (acquisition of new mutations) and epigenetic (modulation of gene expression) mechanisms that underlie tumor survival, metastasis, and resistance to therapy; also known as plasticity. Over the past two decades, my lab has focused on understanding the cellular stress response, particularly the contribution of kinases and ubiquitin ligases. Our studies established a number of paradigms in stress adaptation, with demonstrated significance for the development, progression, and drug resistance of both melanoma and prostate cancer. We defined how subcellular localization dictates the oncogenic or tumor suppressor activity of ATF2, and showed that this is regulated by the AGC kinase PKC?. Based on this discovery we performed a screen for inhibitors of this transcription factor-ostensibly undruggable targets- based on altered subcellular localization. Our other recent discovery of a spliced form of ATF2 that exhibits a gain-of-function phenotype will enable us to further redefine the function of ATF2 in melanoma. Further, we identified a mechanism of rewired signaling in which ERK impacts JNK with concomitant effects on PDK1, the master regulator of AGC kinases. This led us to demonstrate the key role played by PDK1 in melanoma. Our future studies will continue to investigate how PDK1 and its downstream targets contribute to melanoma metastasis and drug resistance. Our discovery that the ubiquitin ligases Siah1/2 control the hypoxia response revealed their roles in melanoma and the most aggressive forms of prostate cancer. Siah1/2 also control stress response signaling, establishing a mechanism for commitment to cell death under ischemic conditions. This established the basis upon which we will develop and evaluate first-in-class Siah inhibitors for prostate cancer and melanoma metastasis and resistance. We also recently determined that the RNF5 ubiquitin ligase regulates both autophagy and glutamine metabolism and established a new method to stratify breast cancer patients to select therapies. Lastly, the discovery that RNF125 ubiquitin ligase is a key regulator of melanoma resistance to BRAF inhibitors will drive an investigation in pancreatic cancer, a fraction of which carry mutated RNF125. Collectively, our discoveries reveal that the tumor cell response to stress, which underlies their plasticity, involves the cooperation between rewired signaling and genetic lesions. Our proposed studies will establish novel mechanisms underlying tumor plasticity, enabling the development of novel agents for predicting, monitoring, and preventing tumor metastasis and resistance.